Synthesis and biological evaluation of bicyclic nucleosides as inhibitors of M. tuberculosis thymidylate kinase.

Ineke van Daele (1) , Hélène Munier-Lehmann (2) , Pieter M S Hendrickx (3) , Gilles Marchal (4) , Pierre Chavarot (4) , Matheus Froeyen (5) , Li Qing (1) , José C Martins (3) , Serge van Calenbergh (1)

1 Laboratory for Medicinal Chemistry-FWW
2 Chimie Organique
3 NMR and Structure Analysis Unit
4 Immunothérapie
5 Laboratory of Medicinal Chemistry

Herein we describe the synthesis and conformational analysis of a series of bicyclic thymidine derivatives and their evaluation as inhibitors of thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKmt), based on previously discovered bicyclic sugar nucleosides. With a K(i) value of 2.3 microm, 1-[3-aminomethyl-3,5-dideoxy-2-O,6-N-(thiocarbonyl)-beta-D-ribofuranosyl]thymine emerged as the most potent TMPK inhibitor of this series. Moreover, this promising compound displays inhibitory potency against Mycobacteria cultures with an IC(99) value of 100 microg mL(-1), thus promoting TMPKmt for the first time as a validated target for further inhibitory design. Attempts to rationalise the observed structure-activity relationship (SAR) involving molecular modelling and conformational analysis are described.

Ineke van Daele, Hélène Munier-Lehmann, Pieter M S Hendrickx, Gilles Marchal, Pierre Chavarot, et al.. Synthesis and biological evaluation of bicyclic nucleosides as inhibitors of M. tuberculosis thymidylate kinase.. ChemMedChem, 2006, 1 (10), pp.1081-90. ⟨10.1002/cmdc.200600028⟩. ⟨pasteur-00166946⟩